A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel

Armstrong, Nigel; Olaye, Andrew; Noake, Caro; Pang, Francis

doi:10.1186/s13023-023-02814-2

Orphanet Journal of Rare Diseases

Table 1 Summary of population characteristics

From: A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel

Study ID (sample size)	Symptom status	MLD type	Baseline ARSA (nmol/hr/mg) in PMBC	Age at diagnosis	Age at symptom onset	Age on treatment initiation/initial assessment	Gender—male/female	Data for population subgroups reported?
Bley 2013 [18] (n = 9)*	Mixed	J	NR	NR	NR	NR	NR	No
Bohringer 2010 [19] (n = 8)*	Mixed	Paediatric	NR	NR	NR	Range 7 months–15 years	NR	No
Boucher 2015 [21] (n = 31)	Mixed	LI to J^a	Mean 8.84 at treatment (n = 26)	Mean 8.45 years (n = 31)	Range 0.83–26.3 years	Mean 9.05 years	9 (29%)/22 (71%)	LI (n = 4); J (n = 27)
EUROCORD 2018 [22] (n = 60 MLD)	Mixed	LI to J^b	NR	NR	NR	Median 4.3 years (0.1–22.7 years)	NR	No
Groeschel 2016 [16]* (n = 65)	Mixed	J^a	NR	NR	Mean 7 years	Median 7 years (1.5–18.2 years)/Mean 8.7 years	33 (50.8%)/32 (49.2%)	No
Kehrer 2014 [26]*^^ (n = 59)	Mixed	LI to LJ^{a^}	NR	NR	Median 17 months (9–27 months) LI group (n = 23) Median 76 (32–162 months) J group (n = 36)	NR	32 (54.2%)/27 (45.8%)	LI (n = 23); J (n = 36)
LDM/1 study [25]** (n = 41)	NR/unclear	LI to LJ	NR	NR	< 15 months–14 years	NR	19 (46%)/22 (54%)	LI (n = 22); EJ (n = 14); LJ (n = 5)
Martin 2013 [23] (n = 27)	Mixed	LI to LJ^{c^}	NR	Mean 7 years (range 0–16.1 years)	NR	Median 5.2 years	18 (66.7%)/9 (33.3%)	LI (n = 10); J (n = 17)
Fumagalli et al. 2022 (Atidarsagene arm) (n = 29) [13]	Mixed	LI to EJ^d	NR	NR	NR	Mean (SD) 12.81(4.3) months—LI (n = 16) 65.86 (33.4) months—EJ (n = 13)	16 (55%)/13 (45%)	LI (n = 16); EJ (n = 13)
Fumagalli et al. 2022 (Natural history arm) [13] (n = 31)	Symptomatic at enrolment	LI to EJ^d	NR	NR	NR	Mean (SD) 20.64 (4.7) months—LI (n = 19) 51.98 (19.2) months—EJ (n = 12)	13 (42%)/18 (58%)	LI (n = 19); EJ (n = 12)
Prasad 2008 [24] (n = 15)	NR/unclear	Paediatric	NR	NR	NR	NR	NR	No
Singh 2012 [20] (n = 11)	NR/unclear	Paediatric^e	NR	NR	NR	NR	NR	No
van Rappard 2016 [17] (n = 7)	NR/unclear	LI to J^f	NR	NR	NR	NR	NR	No

The data only considers those patients with paediatric MLD that are eligible for inclusion in this review; data relevant to adult onset and any other diseases are not considered in this summary
If no symbol the authors have not defined ages for the different MLD types
Mixed—a mixture pre-symptomatic and symptomatic patients
Paediatric—patients were children but not reported whether disease was infantile and/or juvenile type
ARSA arylsulfatase A, EJ early juvenile, J juvenile, LI late infantile, LJ late juvenile, I infantile, n number of participants, MLD metachromatic leukodystrophy, mth month, NR not reported, PMBC peripheral mononuclear blood cells, SD standard deviation, yr year
*Indicates that there is a possibility of overlap with populations reported in other studies based in German study centres and/or using the LEUKONET database
**Indicated that there is a possibility of overlap of patients between two studies (i.e., LDM/1 study and the natural history study arm of Fumagalli et al. 2022), however, the actual number is unclear
^LJ population is no longer of primary relevance to the proposed treatment indication for Atidarsagene
^^One additional paper was identified during the 2021 update which included more patients (LI: n = 35; EJ: n = 18; LJ: n = 28) and longer follow-up (the actual length was not reported). The overlap between previously reported patients and the new publication is not clearly described in text, thus, the results are included in Appendix 13
^aBased on following MLD definitions: LI < 30 months; J 30 months–15 years; Adult disease ≥ 16 years
^bBased on following MLD definitions: LI 0–4 years; EJ 4–6 years; LJ 6–16 years; Adult disease > 16 years
^cBased on following MLD definitions: LI 0.5-4 years; EJ 4–6 years; LJ 6–16 years); Adult disease > 16 years
^dBased on the following MLD definitions: LI presence of 2 of the following 3 criteria: Age at onset of symptoms in the older sibling(s) ≤ 30 months; Two null (0) mutant ARSA alleles; Peripheral neuropathy at ENG study (NCV Index < 2 SD below normal range). EJ in the presence of 2 of the following 3 criteria: Age at onset of symptoms in the subject or older sibling(s) between 30 months and 6 years (i.e., had not celebrated 7th birthday); One null (0) and 1 R mutant ARSA allele(s); Peripheral neuropathy at ENG study
^eBased on the following definition: < 16 years
^fBased on the following MLD definitions: LI < 30ths; J 2.5–16 years; Adult > 16 years

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